Implantable suction cup composites and implants comprising same

ABSTRACT

Described herein are implantable composites, kits comprising the composites, implant devices comprising the composites, and methods of making and using same, including point of use methods.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is based upon and claims the benefit of priority fromprior U.S. Provisional Application No. 61/140,486, filed Dec. 23, 2008,the entire contents of which are incorporated herein by reference.

BACKGROUND

In medicine, certain disorders and conditions require medical implants.Medical implants are often used to replace a damaged biological tissueor fluid, augment or enhance a biological process, enhance the healingof a surgical site, deliver a drug to a localized site within a subject,or perform another biological or structural role. Implants can even benecessary to keep a patient alive. Unfortunately, problems can ariseduring an implant surgery, or after a patient has received the medicalimplant. In some instances, the implant can impair healing of thesurgical site. For example, the surface of the implant can recruitcellular debris and other biological material that can become infectedwith bacteria, fungi, or other infectious agents. The subject's immunesystem can also recognize the implant as a foreign body and attempt tofight the implant using natural defenses. This often lowers the strengthof the subject's immune system and can lead to further serious problems,such as periprosthetic infections, or other infections at or near thesurgical implant site.

Accordingly, it can also be desirable to deliver a bioactive agent at ornear the tissue adjacent the implant site. Such a bioactive agent canhelp prevent at least some of the aforementioned problems associatedwith implants, or enhance the function of the implant itself.Unfortunately, configuring each implant to be capable of locallydelivering a bioactive agent is not always possible or practical. Forexample, regulations for the manufacture of drug products differsignificantly from the regulations for the manufacture of medicaldevices.

As such, a need exists for composites that can be applied to an implantor implanted into a subject that effectively provide a bioactive agentat or near tissue adjacent the implant site. These needs and other needsare satisfied by the present invention.

SUMMARY

Described herein are implantable composites, kits comprising theimplantable composites, and implant devices comprising the implantablecomposites. In one aspect, disclosed are point of use applications,wherein a bioactive agent is applied to a medical device close to thetime of use, which allows for the separate and more rapid development ofthe bioactive agent and the implant device, such that the quality orefficacy of the final implant device is not unduly compromised.

In one aspect, the implantable composite comprises a cup membercomprising a resilient biocompatible polymer and a bioactive agent;wherein the cup member defines a cavity and has a substantially planarrim;

In a further aspect, implant devices comprising the implantablecomposites on a surface thereof the device are disclosed. In one aspect,an implant device comprises a disclosed implantable composite adhered toat least a portion of the implant device.

Also disclosed are methods of applying the implantable composites to animplant device, the method comprising securing the implantable compositeonto a surface of an implant device, substantially close to the timewhen the implant device is implanted in a subject.

The advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or may be learned by practice of the aspects describedbelow. The advantages described below will be realized and attained bymeans of the elements and combinations particularly pointed out in theappended claims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a drawing of an exemplary implantable composite.

FIG. 2 is a drawing of an exemplary implant device comprising animplantable composite adhered thereto the device.

DETAILED DESCRIPTION

Before the present compounds, compositions, composites, articles,devices and/or methods are disclosed and described, it is to beunderstood that the aspects described below are not limited to specificcompounds, compositions, composites, articles, devices, methods, or usesas such may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularaspects only and is not intended to be limiting.

In this specification and in the claims that follow, reference will bemade to a number of terms that shall be defined to have the followingmeanings:

Throughout this specification, unless the context requires otherwise,the word “comprise,” or variations such as “comprises” or “comprising,”will be understood to imply the inclusion of a stated integer or step orgroup of integers or steps but not the exclusion of any other integer orstep or group of integers or steps.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a bioactive agent” includes mixtures of two or more suchagents, and the like.

“Optional” or “optionally” means that the subsequently described eventor circumstance can or cannot occur, and that the description includesinstances where the event or circumstance occurs and instances where itdoes not.

Ranges may be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint.

A weight percent of a component, unless specifically stated to thecontrary, is based on the total weight of the formulation or compositionin which the component is included.

The term “resilient polymer” refers to a polymer that at least partiallyresists deformation such that once deformed, the polymer returns atleast partially, completely, or in the direction of, its non-deformedstate, prior to the deformation.

The term “biocompatible” refers a substance that is substantiallynon-toxic to a subject.

“Biodegradable” is generally referred to herein as a material that willerode to soluble species or that will degrade under physiologicconditions to smaller units or chemical species that are, themselves,non-toxic (biocompatible) to the subject and capable of beingmetabolized, eliminated, or excreted by the subject.

A “bioactive agent” refers to an agent that has biological activity. Thebiological agent can be used to treat, diagnose, cure, mitigate, prevent(i.e., prophylactically), ameliorate, modulate, or have an otherwisefavorable effect on a disease, disorder, infection, and the like. A“releasable bioactive agent” is one that can be released from adisclosed implantable composite. Bioactive agents also include thosesubstances which affect the structure or function of a subject, or apro-drug, which becomes bioactive or more bioactive after it has beenplaced in a predetermined physiological environment.

Disclosed are compounds, compositions, and components that can be usedfor, can be used in conjunction with, can be used in preparation for, orare products of the disclosed methods and compositions. These and othermaterials are disclosed herein, and it is understood that whencombinations, subsets, interactions, groups, etc. of these materials aredisclosed that while specific reference of each various individual andcollective combinations and permutation of these compounds may not beexplicitly disclosed, each is specifically contemplated and describedherein. For example, if a number of different polymers and agents aredisclosed and discussed, each and every combination and permutation ofthe polymer and agent are specifically contemplated unless specificallyindicated to the contrary. Thus, if a class of molecules A, B, and C aredisclosed as well as a class of molecules D, E, and F and an example ofa combination molecule, A-D is disclosed, then even if each is notindividually recited, each is individually and collectivelycontemplated. Thus, in this example, each of the combinations A-E, A-F,B-D, B-E, B-F, C-D, C-E, and C-F are specifically contemplated andshould be considered disclosed from disclosure of A, B, and C; D, E, andF; and the example combination A-D. Likewise, any subset or combinationof these is also specifically contemplated and disclosed. Thus, forexample, the sub-group of A-E, B-F, and C-E are specificallycontemplated and should be considered disclosed from disclosure of A, B,and C; D, E, and F; and the example combination A-D. This conceptapplies to all aspects of this disclosure including, but not limited to,steps in methods of making and using the disclosed compositions. Thus,if there are a variety of additional steps that can be performed it isunderstood that each of these additional steps can be performed with anyspecific embodiment or combination of embodiments of the disclosedmethods, and that each such combination is specifically contemplated andshould be considered disclosed.

Described herein are implantable composites that can be applied to animplant device, or to a tissue or fluid of a subject. The implantablecomposites can release a bioactive agent into the subject. Thecomposites described herein allow for controlled-release,extended-release, modified-release, sustained-release,pulsatile-release, delayed-release, or programmed-release of thebioactive agent.

In one aspect, the implantable composite comprises a cup member defininga cavity and having a substantially planar rim, wherein the cup membercomprises a resilient biocompatible polymer; wherein the resilientbiocompatible polymer comprises a bioactive agent disposed therein thepolymer. In one aspect, the rim is substantially planar. In a furtheraspect, the rim becomes substantially planar when contacting a surface.Thus, in certain aspects, the rim is substantially non-planar, but iscapable of becoming planar when contacting a surface.

With reference to FIG. 1, the cup member 110 of an exemplary implantablecomposite 100 comprises at least one convex surface, as shown, such thatthe cup member defines a cavity 120 that opposes the convex surface. Toenable the cup member to adhere to a contacting surface, the rim 130 ofthe cup member is substantially planar. In one aspect, the disclosedimplantable composite functions as a suction cup. In one aspect, theconvex surface may need to only be slightly convex, or have a slightcurvature.

The implantable composites can have any desired size. In general, thesize selection of the implantable composite can be influenced by thedesired loading of the bioactive agent. Generally, the more bioactiveagent that is desired, the larger the implantable composite will be. Thesize can also be selected so as to provide the desired releaseproperties of the implantable composite. In addition, when theimplantable composite is applied to an implant device, the size of theimplant device can be of importance when selecting the size of theimplantable composite. For example, it can be desirable for portions ofthe implant device surface to remain exposed. In these instances, thesize of the implant can be selected so as to not completely cover theimplant device surface.

The implantable composites can have any desired size. For example, theimplantable composites can have diameters (the greatest distance acrossthe cavity defined by the cup member) including without limitation offrom about 1 cm to about 50 cm or greater, from about 5 cm to about 25cm, or from about 7 cm to about 15 cm, including those implantablecomposites comprising cavities having a diameter of about 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, or 45 cm,or larger. Additionally, the implantable composites can have diametersof less than about 1 cm, including for example, from about 0.1 micronsto about 10 mm, or from about 0.1 microns to about 1 cm. Likewise, theimplantable composites can have any desired cavity depth, which can, invarious aspects, depend on the desired adhesion strength of theimplantable composite once applied to a contacting surface. In oneaspect, the implantable composites can have a cavity depth (i.e., thegreatest cavity depth) of from about 0.1 microns to about 500 cm orgreater, from about 5 microns to about 400 cm, from about 20 microns toabout 200 cm, or from about 50 microns to about 100 cm, including thoseimplantable composites having cavity depths of about 0.1 microns, 1micron, 50 microns, 100 microns, 200 microns, 1 mm, 5 mm, 10 mm, 20 mm,50 mm, 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 8 cm, 10 cm, 20 cm, 30 cm, 40 cm,50 cm, 60 cm, 70 cm, 80 cm, 90 cm, 100 cm, 150 cm, 200 cm, 250 cm, 300cm, 350 cm, 400 cm, 450 cm, or 500 cm or greater.

The cup member can also have any desired thickness. In one aspect, thecup member can be as thin as a thin film, for example, having athickness of from about 50 nm (or less) to about 1000 nm, or greater. Inother aspects, the cup member can have a larger thickess, includingwithout limitation thicknesses from about 1000 nm to about 500 cm, orfrom about 5 cm to about 100 cm, or from about 10 cm to about 80 cm, orfrom about 20 cm to about 50 cm, or larger.

The cup member can have any desired shape. In one aspect, the planar rimhas a shape that is substantially circular, substantially rectangular,or substantially elliptical (oval-like).

In one aspect, the cup member can comprise a polymer with a mechanicalproperty which enables the cup member to be deformed when contacting acontact surface. The polymer should be at least partially resilient, soas to be capable of recovering from deformation to form a seal thatadheres the implantable composite to the contacting surface.

In one aspect, the polymer can be an elastomer. Elastic polymers arethose that can undergo a reversible elongation at a relatively lowstress. Such polymers include without limitation amorphous polymers,polymers with low glass transition temperatures (T_(g)), polymers withhigh polymer chain mobility, cross-linked polymers, or a combinationthereof. In one aspect, suitable polymers are those that aresubstantially amorphous and have a low T_(g). Suitable glass transitiontemperatures include, without limitation, about 25° C. or less, about15° C. or less, about 10° C. or less, about 0° C. or less, about −10° C.or less, about −20° C. or less, about −30° C. or less, about −40° C. orless, about −50° C. or less, about −60° C. or less, about −70° C. orless, or less than −70° C. In a further aspect, suitable polymers arethose that are cross-linked. The degree of cross-linking for an elasticpolymer can be typically selected based on the desired resilience of thecup member. Generally, at least some degree of cross-linking can beuseful to achieve relatively rapid deformation and nearly completereversibility, effective to form a seal on a contacting surface.

Suitable elastic polymers can have a relatively low initial forcemodulus (e.g., less than 100 N/cm), so that the polymer can be expandedwithout an inconvenient amount of force. Typically, however, the forcemodulus should increase beyond the initial force modulus upon expansionof the polymer. In certain aspects, to maintain high strength at a highexpansive force, a polymer can be cross-linked, as discussed above,and/or can comprise biocompatible filler materials which add strength tothe. Additionally, the polymer can be engineered to undergo a smallamount of crystallization at high elongation, which can add strength tothe polymer during forceful expansion.

In a further aspect, the cup member comprises a less reslient polymer,such as a semi-rigid polymer, or a polymer that is not an elastomer, butalso not as rigid as a hard fiber. To that end, in some aspects, the cupmember should be flexible enough to allow for the implantable compositeto be deformed and secured to a contacting surface. In one aspect, thecup member can be a plastic, such as a resilient, flexible plastic.Suitable flexible plastics are those that exhibit moderate to highranges of crystallinity. Typically, a flexible plastic has a forcemodulus of from about 10,000 N/cm² to about 400,000 N/cm², with tensilestrengths of from about 1000 N/cm² to about 10,000 N/cm². In one aspect,a flexible plastic can have an ultimate elongation percentage of fromabout 10% to about 1000%. For example, polyethylene is a typicalflexible plastic with a tensile strength of about 2500 N/cm², a forcemodulus of about 20,000 N/cm², and an ultimate elongation of about 500%.Other typical flexible plastics include without limitation polypropeneand poly(hexamethylene adipamide). Additionally, those polymersdiscussed below can be engineered (e.g., cross-linked, or processed withadditives) to provide the desired mechanical properties of theimplantable composite, for example, flexibility and rigidity.

The cup member used with the implantable composites can comprise anybiocompatible, biodegradable, or non-biodegradable polymer. The polymersdisclosed herein can be homopolymers or copolymers. The polymers can beblock or blocky co- or ter-polymers, random co- or ter-polymers, starpolymers, or dendrimers. Any desired molecular weight polymer can beused, depending on the desired properties of the implantable composite.In certain aspects, if a high strength implantable composite is desired,then high molecular weight polymers can be used, for example, to meetstrength requirements. In other aspects, low or medium molecular weightpolymers can be used when, for example, when resorption time of thepolymer, rather than material strength is desired. In one aspect, thepolymer can be present as a blend of two or more polymers.

The molecular weight of the polymer can be selected so as to provide adesired property of the implantable composite. In certain aspects, theimplantable composite can be provided by forming a molded composite ofthe polymer. In such aspects, the molecular weight should be such toallow a sufficient molded composite to form. The molecular weight shouldalso be suitable to allow the implantable composite to be resilientlyexpanded. The molecular weight of a polymer is also important from thepoint of view that molecular weight influences the biodegradation rateof the polymer. For a diffusional mechanism of bioactive agent release,the polymer should remain intact until all of the drug is released fromthe polymer and then degrade. The drug can also be released from thepolymer as the polymer bioerodes. By an appropriate selection ofpolymeric materials a polymer formulation can be made such that theresulting biodegradable polymer exhibits both diffusional release andbiodegradation release properties. Molecular weights can be measured bymethods known in the art, including gel permeation chromatography,viscosity, light scattering, among other methods.

The implantable composite can be formulated so as to degrade within adesired time interval, once present in a subject. In some aspects, thetime interval can be from about less than one day to about 1 month.Longer time intervals can extend to 6 months, including for example,polymer matrices that degrade from about ≧0 to about 6 months, or fromabout 1 to about 6 months. In other aspects, the polymer can degrade inlonger time intervals, up to 2 years or longer, including, for example,from about ≧0 to about 2 years, or from about 1 month to about 2 years.

The desired bioactive agent release mechanism can influence theselection of the polymer. A biodegradable polymer can be selected so asto release or allow the release of a bioactive agent therefrom at adesired lapsed time after the implantable composite has been implantedinto a subject. For example, the polymer can be selected to release orallow the release of the bioactive agent prior to the bioactive agentbeginning to diminish its activity, as the bioactive agent begins todiminish in activity, when the bioactive agent is partially diminishedin activity, for example at least 25%, at least 50% or at least 75%diminished, when the bioactive agent is substantially diminished inactivity, or when the bioactive agent is completely gone or no longerhas activity.

In one aspect, the polymer can be one or more of polyesters,polyhydroxyalkanoates, polyhydroxybutyrates, polydioxanones,polyhydroxyvalerates, polyanhydrides, polyorthoesters, polyphosphazenes,polyphosphates, polyphosphoesters, polydioxanones, polyphosphoesters,polyphosphates, polyphosphonates, polyphosphates, polyhydroxyalkanoates,polycarbonates, polyalkylcarbonates, polyorthocarbonates,polyesteramides, polyamides, polyamines, polypeptides, polyurethanes,polyalkylene alkylates, polyalkylene oxalates, polyalkylene succinates,polyhydroxy fatty acids, polyacetals, polycyanoacrylates, polyketals,polyetheresters, polyethers, polyalkylene glycols, polyalkylene oxides,polyethylene glycols, polyethylene oxides, polypeptides,polysaccharides, or polyvinyl pyrrolidones. Other non-biodegradable butdurable polymers include without limitation ethylene-vinyl acetateco-polymer, polytetrafluoroethylene, polypropylene, polyethylene, andthe like. Likewise, other suitable non-biodegradable polymers includewithout limitation silicones and polyurethanes.

In a further aspect, the polymer can be a poly(lactide), apoly(glycolide), a poly(lactide-co-glycolide), a poly(caprolactone), apoly(orthoester), a poly(phosphazene), a poly(hydroxybutyrate) or acopolymer containing a poly(hydroxybutarate), apoly(lactide-co-caprolactone), a polycarbonate, a polyesteramide, apolyanhydride, a poly(dioxanone), a poly(alkylene alkylate), a copolymerof polyethylene glycol and a polyorthoester, a biodegradablepolyurethane, a poly(amino acid), a polyamide, a polyesteramide, apolyetherester, a polyacetal, a polycyanoacrylate, apoly(oxyethylene)/poly(oxypropylene) copolymer, polyacetals, polyketals,polyphosphoesters, polyhydroxyvalerates or a copolymer containing apolyhydroxyvalerate, polyalkylene oxalates, polyalkylene succinates,poly(maleic acid), and copolymers, terpolymers, combinations, or blendsthereof.

In a still further aspect, useful biodegradable polymers are those thatcomprise one or more residues of lactic acid, glycolic acid, lactide,glycolide, caprolactone, hydroxybutyrate, hydroxyvalerates, dioxanones,polyethylene glycol (PEG), polyethylene oxide, or a combination thereof.In a still further aspect, useful biodegradable polymers are those thatcomprise one or more residues of lactide, glycolide, caprolactone, or acombination thereof.

In one aspect, useful biodegradable polymers are those that comprise oneor more blocks of hydrophilic or water soluble polymers, including, butnot limited to, polyethylene glycol, (PEG), or polyvinyl pyrrolidone(PVP), in combination with one or more blocks another biocompabible orbiodegradable polymer that comprises lactide, glycolide, caprolactone,or a combination thereof.

In specific aspects, the biodegradable polymer can comprise one or morelactide residues. To that end, the polymer can comprise any lactideresidue, including all racemic and stereospecific forms of lactide,including, but not limited to, L-lactide, D-lactide, and D,L-lactide, ora mixture thereof. Useful polymers comprising lactide include, but arenot limited to poly(L-lactide), poly(D-lactide), and poly(DL-lactide);and poly(lactide-co-glycolide), including poly(L-lactide-co-glycolide),poly(D-lactide-co-glycolide), and poly(DL-lactide-co-glycolide); orcopolymers, terpolymers, combinations, or blends thereof.Lactide/glycolide polymers can be conveniently made by meltpolymerization through ring opening of lactide and glycolide monomers.Additionally, racemic DL-lactide, L-lactide, and D-lactide polymers arecommercially available. The L-polymers are more crystalline and resorbslower than DL-polymers. In addition to copolymers comprising glycolideand DL-lactide or L-lactide, copolymers of L-lactide and DL-lactide arecommercially available. Homopolymers of lactide or glycolide are alsocommercially available.

When the biodegradable polymer is poly(lactide-co-glycolide),poly(lactide), or poly(glycolide), the amount of lactide and glycolidein the polymer can vary. In a further aspect, the biodegradable polymercontains 0 to 100 mole %, 40 to 100 mole %, 50 to 100 mole %, 60 to 100mole %, 70 to 100 mole %, or 80 to 100 mole % lactide and from 0 to 100mole %, 0 to 60 mole %, 10 to 40 mole %, 20 to 40 mole %, or 30 to 40mole % glycolide, wherein the amount of lactide and glycolide is 100mole %. In a further aspect, the biodegradable polymer can bepoly(lactide), 95:5 poly(lactide-co-glycolide) 85:15poly(lactide-co-glycolide), 75:25 poly(lactide-co-glycolide), 65:35poly(lactide-co-glycolide), or 50:50 poly(lactide-co-glycolide), wherethe ratios are mole ratios.

In a further aspect, the polymer can be a poly(caprolactone) or apoly(lactide-co-caprolactone). In one aspect, the polymer can be apoly(lactide-caprolactone), which, in various aspects, can be 95:5poly(lactide-co-caprolactone), 85:15 poly(lactide-co-caprolactone),75:25 poly(lactide-co-caprolactone), 65:35poly(lactide-co-caprolactone), or 50:50 poly(lactide-co-caprolactone),where the ratios are mole ratios.

In one aspect, the implantable composite can comprise a terpolymer. Inone aspect, the polymer can be a terpolymer such as those terpolymersdisclosed in U.S. patent application Ser. No. 12/269,135, filed Nov. 12,2008, (U.S. Patent Publication No. 2009/0124535) which is incorporatedherein by this reference for all of its teachings of terpolymers and isconsidered part of this disclosure.

It is understood that any combination of the aforementionedbiodegradable polymers can be used, including, but not limited to,copolymers thereof, mixtures thereof, or blends thereof. Likewise, it isunderstood that when a residue of a biodegradable polymer is disclosed,any suitable polymer, copolymer, mixture, or blend, that comprises thedisclosed residue, is also considered disclosed. To that end, whenmultiple residues are individually disclosed (i.e., not in combinationwith another), it is understood that any combination of the individualresidues can be used. Further, any of the above polymers can beprocessed (e.g., cross-linked to a desired level, to achieve a resilientcup member. An additional cross-linking agent can be used, and/orradical, cation, or anion cross-linking of the existing polymer can beused.

If desired, an adhesive, which can, in various aspect, be separate fromthe cup member, or can be part of the cup member itself, can be presenton the contacting rim of a disclosed implantable composite, that willcontact the implant device surface, or the tissue of fluid of thesubject. The adhesive can be any desired adhesive. In certain aspects,the cup member itself can comprise a tacky polymer, which functions asan adhesive to which an implant device, or tissue or fluid of thesubject can adhere. Methods of making the above disclosed polymers tackyare known in the art. Addititives for example, can be added to provide atacky polymer that can be adhesive. In one aspect, tacky polymers can bethose that comprise a T_(g) of less than about room temperature,including those polymers disclosed above which have glass transitiontemperatures of less than about room temperature. Thus, in certainaspects, the resiliently expandable polymer can contact a disclosedimplant device, tissue or fluid of a subject both elastically andadhesively, through the use of a tacky polymer. Other suitableadhesives, other than the polymer itself, include without limitationthermoplastics, glycoproteins, mucopolysaccharides, bioadhesives,carbohydrates, starches, dextrin, sugars, gelatin, epoxy, acrylics,rubber, silicones, polyurethanes, pressure sensitive adhesives,polyesters, polyethers, polychloroprene, natural gums, peroxides,silanes, isocyanates, or combinations, mixtures, and blends thereof.

In one aspect, the adhesive can be a biodegradable adhesive, includingwithout limitation, poly(lactide-co-caprolactone),poly(glycolide-co-caprolactone), or combinations, mixtures, and blendsthereof.

The adhesive can be applied to the rim of the cup member through methodsknown in the art. Adhesives can be applied, for example, throughspin-coating, drop-casting, brushing, or spraying an adhesivecomposition onto the first surface of the polymer.

In other aspects, the implantable composite does not comprise anadhesive. In a further aspect, the rim of the implantable composite doesnot comprise an adhesive. It will be apparent that the disclosedimplantable composites can be sealed to a contacting surface without theuse of an adhesive.

In one aspect, the rim of the cup member can be moistened, or wetted toenhance the adhesion of the cup member to the contacting surface. Thus,in one aspect, the implantable composite comprises a moistened rim.

In a further aspect, the cup member can comprise an opacifier. For thisaspect, any desired opacifier can be used. An opacifier can be useful toview the implantable composite or the device comprising same in thesubject, through an opacifier signal, such as fluorescence, or forexample, through x-ray among other diagnostic techniques. In one aspect,the opacifier can be without limitation barium sulfate, which can, invarious aspects, make an implant device visible or more visible by animaging technique, such as, for example, x-ray, among others.

As discussed above, the implantable composite comprises a bioactiveagent. The bioactive agent can be a releasable bioactive agent, i.e., abioactive agent that can be released from the implantable composite. Incertain aspects, the bioactive agent can be in or on the cup member. Ina further aspect, the bioactive agent can be dispersed in the polymer.

Various forms of the bioactive agent can be used, which are capable ofbeing released from the cup member into adjacent tissues or fluids. Tothat end, a liquid or solid bioactive agent can be incorporated into theimplantable composites described herein. The bioactive agents are atleast very slightly water soluble, and preferably moderately watersoluble. The bioactive agents can include salts of the activeingredient. As such, the bioactive agents can be acidic, basic, oramphoteric salts. They can be nonionic molecules, polar molecules, ormolecular complexes capable of hydrogen bonding. The bioactive agent canbe included in the compositions in the form of, for example, anuncharged molecule, a molecular complex, a salt, an ether, an ester, anamide, polymer drug conjugate, or other form to provide the effectivebiological or physiological activity.

Examples of bioactive agents that incorporated into systems hereininclude, but are not limited to, peptides, proteins such as hormones,enzymes, antibodies, antibody fragments, engineered antibodies ofvarious molecular weights, and the like, nucleic acids such as aptamers,iRNA, DNA, RNA, antisense nucleic acid or the like, antisense nucleicacid analogs or the like, low-molecular weight compounds, orhigh-molecular-weight compounds. Bioactive agents contemplated for usein the disclosed implantable composites include anabolic agents,antacids, anti-asthmatic agents, anti-cholesterolemic and anti-lipidagents, anti-coagulants, anti-convulsants, anti-diarrheals,anti-emetics, anti-infective agents including antibacterial andantimicrobial agents, anti-inflammatory agents, anti-manic agents,antimetabolite agents, anti-nauseants, anti-neoplastic agents,anti-obesity agents, anti-pyretic and analgesic agents, anti-spasmodicagents, anti-thrombotic agents, anti-tussive agents, anti-uricemicagents, anti-anginal agents, antihistamines, appetite suppressants,biologicals, cerebral dilators, coronary dilators, bronchiodilators,cytotoxic agents, decongestants, diuretics, diagnostic agents,erythropoietic agents, expectorants, gastrointestinal sedatives,hyperglycemic agents, hypnotics, hypoglycemic agents, immunomodulatingagents, ion exchange resins, laxatives, mineral supplements, mucolyticagents, neuromuscular drugs, peripheral vasodilators, psychotropics,sedatives, stimulants, thyroid and anti-thyroid agents, tissue growthagents, uterine relaxants, vitamins, or antigenic materials.

Other bioactive agents include androgen inhibitors, polysaccharides,growth factors, hormones, anti-angiogenesis factors, dextromethorphan,dextromethorphan hydrobromide, noscapine, carbetapentane citrate,chlophedianol hydrochloride, chlorpheniramine maleate, phenindaminetartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxaminecitrate, phenylephrine hydrochloride, phenylpropanolamine hydrochloride,pseudoephedrine hydrochloride, ephedrine, codeine phosphate, codeinesulfate morphine, mineral supplements, cholestryramine,N-acetylprocainamide, acetaminophen, aspirin, ibuprofen, phenylpropanolamine hydrochloride, caffeine, guaifenesin, aluminum hydroxide,magnesium hydroxide, peptides, polypeptides, proteins, amino acids,hormones, interferons, cytokines, and vaccines.

Representative drugs that can be used as bioactive agents in theimplantable composites include, but are not limited to, peptide drugs,protein drugs, desensitizing materials, antigens, anti-infective agentssuch as antibiotics, antimicrobial agents, antiviral, antibacterial,antiparasitic, antifungal substances and combination thereof,antiallergenics, androgenic steroids, decongestants, hypnotics,steroidal anti-inflammatory agents, anti-cholinergics, sympathomimetics,sedatives, miotics, psychic energizers, tranquilizers, vaccines,estrogens, progestational agents, humoral agents, prostaglandins,analgesics, antispasmodics, antimalarials, antihistamines, cardioactiveagents, nonsteroidal anti-inflammatory agents, antiparkinsonian agents,antihypertensive agents, β-adrenergic blocking agents, nutritionalagents, and the benzophenanthridine alkaloids. The agent can further bea substance capable of acting as a stimulant, sedative, hypnotic,analgesic, anticonvulsant, and the like.

The implantable composite can comprise a large number of bioactiveagents either singly or in combination. Other bioactive agents includebut are not limited to analgesics such as acetaminophen, acetylsalicylicacid, and the like; anesthetics such as lidocaine, xylocaine, and thelike; anorexics such as dexadrine, phendimetrazine tartrate, and thelike; antiarthritics such as methylprednisolone, ibuprofen, and thelike; antiasthmatics such as terbutaline sulfate, theophylline,ephedrine, and the like; antibiotics such as sulfisoxazole, penicillinG, ampicillin, cephalosporins, amikacin, gentamicin, tetracyclines,chloramphenicol, erythromycin, clindamycin, isoniazid, rifampin, and thelike; antifungals such as amphotericin B, nystatin, ketoconazole, andthe like; antivirals such as acyclovir, amantadine, and the like;anticancer agents such as cyclophosphamide, methotrexate, etretinate,and the like; anticoagulants such as heparin, warfarin, and the like;anticonvulsants such as phenytoin sodium, diazepam, and the like;antidepressants such as isocarboxazid, amoxapine, and the like;antihistamines such as diphenhydramine HCl, chlorpheniramine maleate,and the like; hormones such as insulin, progestins, estrogens,corticoids, glucocorticoids, androgens, and the like; tranquilizers suchas thorazine, diazepam, chlorpromazine HCl, reserpine, chlordiazepoxideHCl, and the like; antispasmodics such as belladonna alkaloids,dicyclomine hydrochloride, and the like; vitamins and minerals such asessential amino acids, calcium, iron, potassium, zinc, vitamin B₁₂, andthe like; cardiovascular agents such as prazosin HCl, nitroglycerin,propranolol HCl, hydralazine HCl, pancrelipase, succinic aciddehydrogenase, and the like; peptides and proteins such as LHRH,somatostatin, calcitonin, growth hormone, glucagon-like peptides, growthreleasing factor, angiotensin, FSH, EGF, bone morphogenic protein (BMP),erythopoeitin (EPO), interferon, interleukin, collagen, fibrinogen,insulin, Factor VIII, Factor IX, Enbrel®, Rituxam®, Herceptin®,Leucentis®, Ustekinumab®, denosumab, sclerostin, alpha-glucosidase,Cerazyme/Ceredose®, vasopressin, ACTH, human serum albumin, gammaglobulin, structural proteins, blood product proteins, complex proteins,enzymes, antibodies, monoclonal antibodies, and the like;prostaglandins; nucleic acids; carbohydrates; fats; narcotics such asmorphine, codeine, and the like, psychotherapeutics; anti-malarials,L-dopa, diuretics such as furosemide, spironolactone, and the like;antiulcer drugs such as rantidine HCl, cimetidine HCl, and the like.

The bioactive agent can also be an immunomodulator, including, forexample, cytokines, interleukins, interferon, colony stimulating factor,tumor necrosis factor, and the like; allergens such as cat dander, birchpollen, house dust mite, grass pollen, and the like; antigens ofbacterial organisms such as Streptococcus pneumoniae, Haemophilusinfluenzae, Staphylococcus aureus, Streptococcus pyrogenes,Corynebacterium diphteriae, Listeria monocytogenes, Bacillus anthracis,Clostridium tetani, Clostridium botulinum, Clostridium perfringens.Neisseria meningitides, Neisseria gonorrhoeae, Streptococcus mutans.Pseudomonas aeruginosa, Salmonella typhi, Haemophilus parainfluenzae,Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibriocholerae, Legionella pneumophila, Mycobacterium tuberculosis,Mycobacterium leprae, Treponema pallidum, Leptspirosis interrogans,Borrelia burgddorferi, Campylobacter jejuni, and the like; antigens ofsuch viruses as smallpox, influenza A and B, respiratory synctial,parainfluenza, measles, HIV, SARS, varicella-zoster, herpes simplex 1and 2, cytomeglavirus, Epstein-Barr, rotavirus, rhinovirus, adenovirus,papillomavirus, poliovirus, mumps, rabies, rubella, coxsackieviruses,equine encephalitis, Japanese encephalitis, yellow fever, Rift Valleyfever, lymphocytic choriomeningitis, hepatitis B, and the like; antigensof such fungal, protozoan, and parasitic organisms such as Cryptococcucneoformans, Histoplasma capsulatum, Candida albicans, Candidatropicalis, Nocardia asteroids, Rickettsia ricketsii, Rickettsia typhi,Mycoplasma pneumoniae, Chlamyda psittaci, Chlamydia trachomatis,Plasmodium falciparum, Trypanasoma brucei, Entamoeba histolytica,Toxoplasma gondii, Trichomonas vaginalis, Schistosoma mansoni, and thelike. These antigens may be in the form of whole killed organisms,peptides, proteins, glycoproteins, carbohydrates, or combinationsthereof.

In a specific aspect, wherein the bioactive agent comprises at least oneof an antibiotic, antimicrobial, a growth factor, a growth inhibitor, animmunomodulator, a steroid, or an anti-inflammatory, including withoutlimitation any of those disclosed above.

In a further specific aspect, the bioactive agent comprises anantibiotic. The antibiotic can be, for example, one or more of Amikacin,Gentamicin, Kanamycin, Neomycin, Netilmicin, Streptomycin, Tobramycin,Paromomycin, Ansamycins, Geldanamycin, Herbimycin, Carbacephem,Loracarbef, Carbapenems, Ertapenem, Doripenem, Imipenem/Cilastatin,Meropenem, Cephalosporins (First generation), Cefadroxil, Cefazolin,Cefalotin or Cefalothin, Cefalexin, Cephalosporins (Second generation),Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cephalosporins(Third generation), Cefixime, Cefdinir, Cefditoren, Cefoperazone,Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime,Ceftriaxone, Cephalosporins (Fourth generation), Cefepime,Cephalosporins (Fifth generation), Ceftobiprole, Glycopeptides,Teicoplanin, Vancomycin, Macrolides, Azithromycin, Clarithromycin,Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin,Telithromycin, Spectinomycin, Monobactams, Aztreonam, Penicillins,Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin,Dicloxacillin, Flucloxacillin, Mezlocillin, Meticillin, Nafcillin,Oxacillin, Penicillin, Piperacillin, Ticarcillin, Polypeptides,Bacitracin, Colistin, Polymyxin B, Quinolones, Ciprofloxacin, Enoxacin,Gatifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Norfloxacin,Ofloxacin, Trovafloxacin, Sulfonamides, Mafenide, Prontosil (archaic),Sulfacetamide, Sulfamethizole, Sulfanilimide (archaic), Sulfasalazine,Sulfisoxazole, Trimethoprim, Trimethoprim-Sulfamethoxazole(Co-trimoxazole) (TMP-SMX), Tetracyclines, including Demeclocycline,Doxycycline, Minocycline, Oxytetracycline, Tetracycline, and others;Arsphenamine, Chloramphenicol, Clindamycin, Lincomycin, Ethambutol,Fosfomycin, Fusidic acid, Furazolidone, Isoniazid, Linezolid,Metronidazole, Mupirocin, Nitrofurantoin, Platensimycin, Pyrazinamide,Quinupristin/Dalfopristin, Rifampicin (Rifampin in U.S.), Tinidazole, ora combination thereof. In one aspect, the bioactive agent can be acombination of Rifampicin (Rifampin in U.S.) and Minocycline.

It is contemplated that other components such as, for example,excipients, pharmaceutically carriers or adjuvants, microparticles, andthe like, can be combined with the cup member and/or the bioactiveagent. Thus, in certain aspects, the bioactive agent can be present as acomponent in a pharmaceutical composition. Pharmaceutical compositionscan be conveniently prepared in a desired dosage form, including, forexample, a unit dosage form or controlled release dosage form, andprepared by any of the methods well known in the art of pharmacy. Ingeneral, pharmaceutical compositions are prepared by uniformly andintimately bringing the bioactive agent into association with a liquidcarrier or a finely divided solid carrier, or both. The pharmaceuticalcarrier employed can be, for example, a solid, liquid, or gas. Examplesof solid carriers include lactose, terra alba, sucrose, talc, gelatin,agar, pectin, acacia, magnesium stearate, and stearic acid. Examples ofliquid carriers are sugar syrup, peanut oil, olive oil, and water.Examples of gaseous carriers include carbon dioxide and nitrogen. Otherpharmaceutically acceptable carriers or components that can be mixedwith the bioactive agent can include, for example, a fatty acid, asugar, a salt, a water-soluble polymer such as polyethylene glycol, aprotein, polysacharride, or carboxmethyl cellulose, a surfactant, aplasticizer, a high- or low-molecular-weight porosigen such as polymeror a salt or sugar, or a hydrophobic low-molecular-weight compound suchas cholesterol or a wax.

In certain aspects, the polymer and bioactive agent are combined oradmixed to form a blend or admixture, wherein the bioactive agent isdisposed in the polymer. Admixing methods can be performed usingtechniques known in the art. For example, the polymer and bioactiveagent can be dry blended (i.e., mixing of particulates of the polymerand the agent) using, for example, a Patterson-Kelley V-blender, orgranulated prior to processing.

In one aspect, the processing of the admixture can be performed underconditions such that the agent is intimately mixed or dispersedthroughout the implantable composite. Alternatively, the processing ofthe admixture can be performed under conditions such that the agent islocalized on or in only a portion or portions of the implantablecomposite. To that end, the implantable composite can include areas thatare rich in bioactive agent, and areas that are not as rich. In oneaspect, the cup member can comprise a bioactive agent in a certainregion of the cup member, such as the center for example, that can besurrounded by a rate-releasing controlling membrane. The admixture canbe processed by a variety of techniques, such as, for example, meltextruding, injection molding, compression molding, or roller compactingthe admixture into a desired shape or structure.

Other suitable pharmaceutical carriers include without limitationmicroparticles. The term “microparticle” is used herein to refergenerally to a variety of substantially structures having sizes fromabout 10 nm to 2000 microns (2 millimeters) and includes microcapsule,microsphere, nanoparticle, nanocapsule, nanosphere as well as particles,in general, that are less than about 2000 microns (2 millimeters). Themicroparticle can contain and affect the release of the bioactive agentfrom the implantable composite.

The microparticle can be comprised of any of those polymers mentionedabove or any polymer used in the microparticle art. In general, theabove mentioned polymers can be cross-linked to a certain level, whichthereby can form a microparticle of the polymer, as is known in the art.When a microparticle is present in the implantable composite, themicroparticle can be the same or different as the polymer comprising thebulk of the implantable composite. The implantable composite cancomprise any desired amount of microparticles, including, for example,from about 1 weight % to about 95 weight %, including 5, 10, 20, 30, 40,50, 60, 70, 80, and 90 weight %, relative to the weight of the totalimplantable composite. The microparticle can be combined with theimplantable composite through known methods.

In one aspect, the disclosed microparticles can have an average or meanparticle size of from about 20 microns to about 125 microns. In oneembodiment the range of mean particle size is from about 40 microns toabout 90 microns. In another embodiment the range of mean particle sizesis from about 50 microns to about 80 microns. Particle sizedistributions are measured by laser diffraction techniques known tothose of skill in the art.

In a further aspect, the bioactive agent can be encapsulated,microencapsulated, or otherwise contained within a microparticle. Themicroparticle can modulate the release of the bioactive agent. Themicroparticle can comprise any desired amount of the bioactive agent.For example, the microparticle can comprise 1%, 5%, 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, 95% by weight bioactive agent, relative to theweight of the microparticle, including any range between the disclosedpercentages.

The microparticles can be made using methods known in the art,including, for example, those methods disclosed in U.S. PatentPublication No. 2007/0190154, published Aug. 16, 2007, and U.S. Pat. No.5,407,609 to Tice et al., both of which are incorporated herein in theirentirety by this reference for teachings of microparticle preparationmethods. As will be apparent, depending upon processing conditions, thepolymer used as a starting material in the admixing step may or may notbe the same polymer present in the final implantable composite. Forexample, the polymer during processing may undergo polymerization ordepolymerization reactions, which ultimately can produce a differentpolymer that was used prior to processing. Thus, the term “polymer” asused herein covers the polymers used as starting materials as well asthe final polymer present in the device produced by the methodsdescribed herein.

Also disclosed are kits comprising the implantable composites. The kitcan be comprised one or more disclosed implantable composites, in apackage. In one aspect, the kits can comprise a mixture of the same ordifferent implantable composites. For example, the kit can compriseseveral sets of implantable composites, each having a different or thesame size. Such a kit may be useful for point of use applications of theimplantable composites, wherein one kit, for example, can provideimplantable composites that are compatible in size with a number ofdifferent implant devices.

Also disclosed are implant devices comprising the implantablecomposites. The term “device” is any formulation or article that isgreater than 1 mm in length in at least one dimension of the device. Thedevice can comprise a disclosed implantable composite. In a furtheraspect, the device has one dimension that is from 1 mm to 50 mm, 1.2 mmto 45 mm, 1.4 mm to 42 mm, 1.6 mm to 40 mm, 1.8 mm to 38 mm, or 2.0 mmto 36 mm, 5.0 mm to 33 mm, or 10 mm to 30 mm. In a further aspect, thedevice has one dimension that is greater than 3 cm, even up to orgreater than 10 cm, 20 cm, or even 30 cm.

In one aspect, the implant device comprises a disclosed implantablecomposite contacting at least a portion of the implant device.

The implant device can comprise any shape, such as a rod, a fiber, acylinder, a bead, a ribbon, a disc, a wafer, a free-formed shaped solid,or a variety of other shaped solids. The device can have any regular orirregular shape and can have any cross section like circular,rectangular, triangular, oval, and the like. In a further aspect, thedevice comprises a cylindrical shape, such as a typical shape of animplantable pump.

The implant can be comprised of any suitable material, such as a metal(e.g., titanium), metal composite, organic material, polymeric, or evenceramic material. The surface of the implant can be any shaped surface,and may have a porous, beaded or meshed ingrowth surface, as can bepresent in certain implants.

The implant device can be any type of medical implant. The implantdevices can include, for example, implants for drug delivery, includingdrug delivery pumps; orthopedic implants, including spinal implants,implants for osseointegration or bone repair; medical stents, includingstents with inherent drug delivery capability; prosthetic implants,including breast implants, muscle implants, and the like; dentalimplants; ear implants, including cochlear implants and hearing devices;cardiac implants including pacemakers, catheters, etc.; space fillingimplants; bioelectric implants; neural implants; internal organimplants, including dialysis grafts; defribrillators; monitoringdevices; recording devices; stimulators, including deep brainstimulators, nerve stimulators, bladder stimulators, and diaphragmstimulators; implantable identification devices and information chips;artificial organs; drug administering devices; implantablesensors/biosensors; screws, tubes, rods, plates, or artificial joints.

In a further aspect, the implant device can be at least one of a pump,pacemaker, defribrillator, or stimulator, including deep brainstimulators, nerve stimulators, bladder stimulators, and diaphragmstimulators.

With reference to FIG. 2, an implant device 200 can comprise a firstimplant device surface 210 that comprises an implantable composite 100,which is shown in the absence of an implant device in FIG. 1.

Once the implant device is present in a subject, the implantablecomposite can degrade, allowing the bioactive agent to be released in ornear the tissue that is adjacent the implant site. If desired, aplurality of implantable composites can be applied to the implantdevice. Optionally, the implantable composite can fall off thecontacting surface once inside the subject. In one aspect, theimplantable composite can fall off the contacting surface once thefunction of the implantable composite has been completed, for example,the delivery of the bioactive agent to adjacent tissues or fluids of thesubject.

Other implant devices that may benefit when used with the disclosedimplantable composites include those with one or more active surfaces,e.g., a surface that enhances a connection between a tissue or fluid andthe implant device, or a surface that allows for or enhances woundhealing. To that end, the disclosed implantable composites can beeffective when applied to only a portion of the implant device, allowingfor any active surface to remain exposed and functional when the implantdevice is implanted in a subject.

As discussed above, it can be desirable to deliver a bioactive agent ator near the tissue adjacent an implant site. The bioactive agent canhelp prevent some of the problems associated with implants, such asinfection, or enhance the function of the implant itself. It can also bedesirable to avoid pre-manufacturing an implant device with bioactiveagent releasing capability, as discussed above. It should be appreciatedthat the composites, methods, and kits disclosed herein can allow for apoint of use application of an implantable composite onto the surface ofan implant device, thus obviating the need to pre-manufacture implantdevices having bioactive agent releasing capability.

In one aspect, an implantable composite can be applied to an implantdevice surface close to or during the time of use. For example, animplantable composite can be applied to an implant device by securingthe implantable composite onto the surface of the implant device,substantially close to the time when the implant device is implanted ina subject. In one aspect, the implantable composite can be applied to animplant device in an operating suite, for example, by a physician ornurse.

The implantable composite can be secured to the surface of the implantdevice prior to or after the time when the implant device is implantedin the subject. In one aspect, the implant device comprising theimplantable composite can be implanted into the subject. In a furtheraspect, the implant device can be implanted into the subject, and thenthe implantable composite can be applied to the surface of the implantdevice. When implanting smaller implants, it may be beneficial to firstsecure the implantable composite to the implant device surface beforeimplanting the device in a subject.

In one aspect, the implantable composite can be secured to the surfaceof the implant device on the same day (i.e., within 24 hours) of theimplant surgery, including, for example, within 23 hours, 20 hours, 15hours, 10 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 15minutes, 10 minutes, 5 minutes, 2 minutes, 30 seconds, or during withthe implant surgery itself. In certain aspects, as discussed above, theimplantable composite can remain secured to the device for any desiredtime interval, including without limitation, days, weeks, or longer.

If desired, the implantable composite itself, with or without an implantdevice, can be implanted onto or in a tissue or fluid of a subject. Inone aspect, the implantable composite can be implanted onto or in atissue or fluid that is near or adjacent to an implant site, i.e., asite where an implant device has been implanted, or near or adjacent toa desired implant site.

Typically, before applying the implantable composite to the implantdevice, the implant device surface can be cleaned or treated to removeany surface contaminants and to promote good adhesion of the implantablecomposite. For example, the implantable composite and/or the implantdevice can be sterilized e.g. by autoclaving under water steam. However,in some aspects, care may be needed to avoid irreversibility deformingthe implantable composite, or melting the implantable composite. Theimplantable composite or implant device comprising the implantablecomposite can then be implanted into the subject using known surgicaltechniques. In certain aspects, it can be desirable to store theimplantable composites or kits comprising the composites in a sterilizedcontainer or package. In one aspect, the kit can comprise a sterilizedpackage of the implantable composites.

The disclosed methods can be used with any of the disclosed implantablecomposites comprising a releasable bioactive agent. In one aspect, themethod comprises securing the implantable composite on a contactingsurface of the implant device, or tissue or fluid of a subject. In oneaspect, the substantially planar rim can be applied to a contactingsurface (e.g., a substantially planar contacting surface) of the implantdevice. The application of the implantable composite to a contactingsurface can be carried out using any known means, including withoutlimitation manual deformation of the cup member, which in variousaspects, expels air from within the cavity defined by the cup member. Asthe air is expelled, the rim of the cup member forms a tight seal withthe contacting surface, allowing the cup member to remain adhered to thecontact surface for a desired period of time, including extended periodsof time, depending on the tightness of the formed seal. Such a seal isachieved in a suction cup like manner. Optionally, an adhesive can beapplied to a portion or the entire first surface of the implantablecomposite, or to a portion or the entire implant device surface, to aidin securing the implantable composite to the implant device.Additionally, as discussed above, which can be used with or without anadhesive, the rim of the cup member can be moistened to aid in making aseal to the contacting surface.

The implant device can be implanted in any desired subject. The subjectcan be a vertebrate, such as a mammal, a fish, a bird, a reptile, or anamphibian. The subject of the herein disclosed methods can be, forexample, a human, non-human primate, horse, pig, rabbit, dog, sheep,goat, cow, cat, guinea pig or rodent. The term does not denote aparticular age or sex. Thus, adult and newborn subjects, as well asfetuses, whether male or female, are intended to be covered.

EXAMPLES

The following examples are set forth below to illustrate the methods andresults according to the disclosed subject matter. These examples arenot intended to be inclusive of all aspects of the subject matterdisclosed herein, but rather to illustrate representative methods andresults. These examples are not intended to exclude equivalents andvariations of the present invention which are apparent to one skilled inthe art.

Efforts have been made to ensure accuracy with respect to numbers (e.g.,amounts, temperature, pH, etc.) but some errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,temperature is in ° C. or is at ambient temperature, and pressure is ator near atmospheric. There are numerous variations and combinations ofconditions, e.g., component concentrations, temperatures, pressures, andother reaction ranges and conditions that can be used to optimize theproduct purity and yield obtained from the described process. Onlyreasonable and routine experimentation will be required to optimize suchprocess conditions.

Example 1 Prophetic

In a first Example, Particles of tobramycin (antibiotic) and particlesof polylactide (biocompatible, bioresorbable polymer) are prepared of asuitable size, e.g., about a mean of 500 micron, and blended. Theblended mixture of drug and polymer particles are introduced into atwin-screw, melt extruder. The melt extruder is equipped with arectangular dye such that a molten mixture comprising tobramycin andpolylactide passes through the dye and exits the extruder as molten filmwhich then cools and solidifies into a continuous film. The hardenedfilm contains tobramycin dispersed thoughout the polymer matrix. Theresultant film is then heat pressed against a circular, convex mold toform a cup member with flashing. The flashing or excess film is thenremoved by cutting to make a circular cup member. The cup member ispackaged and terminally sterilized. Just prior to administration, thecup member is removed from the sterile package and pushed onto a medicaldevice, e.g., a deep brain stimulator. To aid adherence the cup membercan be moistened with sterile water or phosphate buffered saline. Oncethe cup member is held in place to the medical device by suction, thedevice is placed inside the patient. Subsequently, extended release oftobramycin from the cup member (drug-eluting film) occurs for a desiredperiod to prevent infection.

Various modifications and variations can be made to the compounds,composites, kits, articles, devices, compositions, and methods describedherein. Other aspects of the compounds, composites, kits, articles,devices, compositions, and methods described herein will be apparentfrom consideration of the specification and practice of the compounds,composites, kits, articles, devices, compositions, and methods disclosedherein. It is intended that the specification and examples be consideredas exemplary.

What is claimed is:
 1. An implantable composite comprising: a deformablesuction cup member, wherein the suction cup member comprises abiodegradable biocompatible polymer and a bioactive agent dispersedwithin the polymer, and wherein the suction cup member defines cavityand has a substantially planar rim, the bioactive agent comprising atleast one of an antibiotic, antimicrobial, a growth factor, a growthinhibitor, an immunomodulator, a steroid, or an anti-inflammatory; thebiodegradable biocompatible polymer comprising one or more residuesselected from the group of lactide, glycolide, and caprolactone; thebiodegradable biocompatible polymer exhibiting a mechanical propertywhich enables the cup member to be deformed when contacting a contactsurface.
 2. The implantable composite of claim 1, wherein the rim has ashape that is substantially circular, substantially rectangular, orsubstantially elliptical.
 3. The implantable composite of claim 1,wherein the suction cup member further comprises an opacifier.
 4. Theimplantable composite of claim 1, wherein the bioactive agent isencapsulated within a microparticle.
 5. The implantable composite ofclaim 1, wherein the substantially planar rim further comprises anadhesive.
 6. The implantable composite of claim 5, wherein the adhesivecomprises a biodegradable adhesive.
 7. The implantable composite ofclaim 6, wherein the biodegradable adhesive comprisespoly(lactide-co-caprolactone), poly(glycolide-co-caprolactone), orcombinations, and mixtures, and blends thereof.
 8. The implantablecomposite of claim 1, the suction cup member comprising a terpolymer. 9.An implant device comprising: an implantable composite; wherein theimplantable composite comprises a deformable suction cup membercomprising a biodegradable biocompatible polymer and a bioactive agentdispersed within the polymer; wherein the suction cup member defines acavity and has a substantially planar rim, the bioactive agentcomprising at least one of an antibiotic, antimicrobial, a growthfactor, a growth inhibitor, an immunomodulator, a steroid, or ananti-inflammatory; the biodegradable biocompatible polymer comprisingone or more residues selected from the group of lactide, glycolide, andcaprolactone; the biodegradable biocompatible, polymer exhibiting amechanical property which enables the cup member to be deformed whencontacting a contact surface.
 10. The implant device of claim 9, thebiodegradable biocompatible polymer comprising a terpolymer.
 11. Theimplant device of claim 9, wherein the implant device comprises a pump,pacemaker, defibrillator, or stimulator.